The present invention relates to substituted 3-amino-2-benzyl-1-phenylpropane derivatives, processes for their preparation, pharmaceutical products containing these compounds, as well as the use of these substances for producing pharmaceutical products.
Pain is one of the main symptoms present in clinical practice, and there is a universal need for effective treatments for pain. The urgent need to provide a patient-oriented and targeted treatment for chronic and non-chronic painful conditions, which is understood to include the successful and satisfactory treatment of pain for patients, is documented in the large number of scientific articles that have recently been published in the field of applied analgesics and in basic research on pain relief. Thus, 1-phenyl-3-dimethylaminopropane compounds having an analgesic effect are known for example from DE-A-44 26 245.
Conventional opioids such as, e.g. morphine are effective in the treatment of severe to extremely severe pain. However, their undesirable side effects include, inter alia, respiratory depression, vomiting, sedation, constipation, as well as tolerance development. Also, they are less effective in neuropathic or incidental painful conditions such as frequently occur, especially in patients with tumours.
Tramadol hydrochloride-(1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol occupies a special position among analgesics acting on the central nervous system, since this active substance has a powerful pain-inhibiting effect without the side effects known in the case of opioids (J. Pharmacol. Exptl. Ther. 267, 33 (1993)).
2-Benzyl-3-dimethylamino-1-phenylpropane and the corresponding methyl iodide are described in J. Am. Chem. Soc., 1966, 88, 5518-5521 as an intermediate product of a xcex3-elimination reaction. The analgesic effect of 1,3-diphenylpropanol derivatives and xcex2-phenylpropiophenone derivatives is described in J. Med. Chem., 1964, 7, S 716-721 and Bull. Soc. Chim. Fr., 1963, 12, 2747-2748, though a detailed investigation has not been carried out however on account of undesirable side effects.
The object of the invention was accordingly to provide analgesically effective substances that are suitable for treating severe pain, in particular for treating chronic and neuropathic pain. Furthermore these active substances should exhibit as few as possible of the side effects of the opioid analgesics, such as for example nausea, vomiting, dependence, respiratory depression and constipation.
According to the invention this is achieved by substituted 3-amino-2-benzyl-1-phenylpropanes of the general formula I, these compounds having a pronounced analgesic effect.
The present invention accordingly provides substituted 3-amino-2-benzyl-1-phenylpropane derivatives of the general formula I, 
wherein
R0 denotes H, OH or a single bond,
R1 denotes H, a C1-10-alkyl, an aryl or an aryl radical bound via a C1-6-alkylene group, preferably denotes H, a C1-3-alkyl or an aryl radical bound via a C1-3-alkylene group,
R2 denotes H, a C1-10-alkyl, an aryl, or an aryl radical bound via a C1-6-alkylene group, preferably denotes H, a C1-3-alkyl or an aryl radical bound via a C1-3-alkylene group,
R3 denotes H, OH, NH2, halogen, OR7, OHR8, CHR9, a C1-10-alkyl, a C2-10-alkenyl, an aryl or an aryl radical bound via a C1-6-alkylene group, and preferably denotes H, F, Cl, a C1-3-alkyl, a C2-3-alkenyl- or an aryl radical bound via a C1-3-alkylene group,
or together with R0 denotes a group xe2x95x90O, xe2x95x90CHR11 or xe2x95x90Nxe2x80x94OH, preferably xe2x95x90O,
R4-radicals, which may be identical or different, denote H, OH, CN, OR7, SR7, halogen, a C1-10-alkyl, a PO(OR10)3, an aryl, a heterocyclyl, an aryl or heterocyclyl radical bound via a C1-6 alkylene group, and preferably denote H, F, Cl, a C1-6-alkyl, an aryl or heterocyclyl radical bound via a C1-3-alkylene group,
R5-radicals, which may be identical or different, denote H, OH, CN, OR7, SR7, halogen, a C1-10-alkyl, a PO(OR10)3, an aryl, a heterocyclyl, or an aryl or heterocyclyl radical bound via a C1-6 alkylene group, and preferably denote H, F, Cl, a C1-6-alkyl or an aryl or heterocyclyl radical bound via a C1-3-alkylene group,
R6-radicals, which may be identical or different, denote H, OH, CN, OR7, SR7, halogen, a C1-10-alkyl, a PO(OR10)3, an aryl, a heterocyclyl, or an aryl or heterocyclyl radical bound via a C1-6 alkylene group, and preferably denote H, F, Cl, a C1-6-alkyl or an aryl or heterocyclyl radical bound via a C1-3-alkylene group,
R7-radicals, which may be identical or different, denote a C1-10-alkyl, an aryl or an aryl radical bound via a C1-6 alkylene group, and preferably denote C1-3-alkyl or an aryl radical bound via a C1-3-alkylene group,
R8 denotes a C1-10-alkyl, an aryl or an aryl radical bound via a C1-6-alkylene group, and preferably denotes a C1-3-alkyl or an aryl radical bound via a C1-3-alkylene group,
R9 denotes OH, halogen, OR10, SR10 or a C1-10-alkyl radical, and preferably denotes F, Cl or a C1-3-alkyl radical,
R10 denotes a C1-10-alkyl or a C4-8-cycloalkyl radical, preferably a C1-3-alkyl radical,
R11 denotes a C1-10-alkyl radical, preferably a C1-3-alkyl radical,
R12-radicals, which may be identical or different, denote H, a C1-10-alkyl, a C4-8-cycloalkyl, an aryl or an aryl radical bound via a C1-6-alkylene group, preferably a C1-3-alkyl radical,
and/or their enantiomers, diastereomers, bases or salts of physiologically compatible acids,
the compounds of the general formula Ixe2x80x2 being excluded 
wherein the radicals are R0 to R6 and the radicals R4xe2x80x2 to R6xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as well as the corresponding methyliodide,
wherein the radicals R0 and R3 together denote the group xe2x95x90O and R1, R2, R4 to R6 and R4 to R6xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 and R3 together denote the group xe2x95x90O, R6 denotes the group OCH3 and R1, R2, R4, R5 and R4xe2x80x2 to R6xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as hydrochloride,
wherein R0 and R3 together denote the group xe2x95x90O, R6xe2x80x2 denotes the group OCH3 and R1, R2, R4 to R6, R4xe2x80x2 and R5xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 and R3 together denote the group xe2x95x90O, R6xe2x80x2 denotes Cl and R1, R2, R4 to R6, R4xe2x80x2 and R5xe2x80x2 denote H, and also the radicals R12 in each case denote CH3,
wherein R0 and R3 together denote the group xe2x95x90O, R5xe2x80x2 and R6xe2x80x2 in each case denote the group OCH3, and R1, R2, R4 to R6 and R4xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as hydrochloride,
wherein R0 and R3 together denote the group xe2x95x90O, R4, R6 and R6xe2x80x2 in each case denote the group OCH3, and R1, R2, R5, R4xe2x80x2 and R5xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as hydrochloride,
wherein R0 denotes OH, R3 denotes H, CH3, unbranched C3H7, unbranched C5H11, cyclohexyl, phenyl or benzyl, and R1, R2, R4 to R6 and R4xe2x80x2 to R6xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochlorides,
wherein R0 denotes OH, R3 denotes C2H5 and R1, R2, R4 to R6 and R4xe2x80x2 to R6xe2x80x2 denote H and also the radicals R12 n each case denote CH3, as well as the corresponding hydrochloride and the corresponding methyliodide,
wherein R0 denotes OH, R3 denotes phenyl, R6 denotes Cl, R1, R2, R4, R5 and R4xe2x80x2 to R6xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 denotes OH, R3 denotes phenyl, R6xe2x80x2 denotes Cl, R1, R2, R4 to R6, R4xe2x80x2 and R5xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 denotes OH, R3 denotes phenyl, R5xe2x80x2 , R6xe2x80x2 in each case denote the group OCH3, R1, R2, R4 to R6 and R4xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as hydrochloride,
wherein R0 denotes OH, R3 denotes phenyl, R6 denotes the group OCH3, R1, R2, R4, R5 and R4xe2x80x2 to R6xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 denotes OH, R3 denotes phenyl, R6xe2x80x2 denotes the group OCH3, R1, R2, R4 to R6, R4xe2x80x2 and R5xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride and the corresponding methyliodide,
wherein R0 denotes OH, R3 denotes phenyl, R6 and R6xe2x80x2 in each case denote the group OCH3, R1, R2, R4, R5, R4xe2x80x2 and R5xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 denotes OH, R6xe2x80x2 denotes OCH3, R1 to R6, R4xe2x80x2 and R5xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0, R1, R2, the radicals R4 to R6, the radicals R4xe2x80x2 to R6xe2x80x2 in each case denote H, the radical R3 denotes phenyl, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R1, R2, the radicals R4 to R6 the radicals R4xe2x80x2 to R6xe2x80x2 in each case denote H, the radicals R3 and R0 together denote the group xe2x95x90CHR11, and also the radical R11 and in each case the radicals R12 denote CH3, as hydrochloride
wherein R1, R2, the radicals R4 to R6, the radicals R4xe2x80x2 to R6xe2x80x2 in each case denote H, the radicals R3 and R0 together denote the group xe2x95x90Nxe2x80x94OH, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride, and
wherein R1, R2, the radicals R4 to R6, the radicals R4xe2x80x2 to R6xe2x80x2 in each case denote H, the radicals R3 and R0 together denote the group xe2x95x90O, and also the radicals R12 in each case denote C2H5, as hydrochloride.
The term alkyl radicals is also understood to mean hydrocarbons substituted at least once, preferably by halogen, particularly preferably by fluorine. If these hydrocarbons contain more than one substituent, then the latter may be identical or different. The alkyl radicals are preferably methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, heptyl, nonyl or decanyl.
The term alkenyl radicals is also understood to mean hydrocarbons substituted at least once, preferably by halogen, particularly preferably by fluorine, and that contain at least one double bond. If the alkenyl radical contains more than one substituent, then the latter may be identical or different. The alkenyl radicals are preferably 2-propenyl, 2-butenyl, 1-methyl-2-propenyl or 2-methyl-2-propenyl.
The term aryl radical is also understood to mean phenyl or naphthyl radicals substituted at least once by an OH, a halogen, preferably F and/or Cl, a CF3, a C1-6 alkyl, a C1-6 alkoxy, a C1-7 cycloalkoxy, a C3-7 cycloalkyl, a C2-6 alkylene or phenyl radical. The phenyl radicals may also be condensed with further rings.
The term heterocyclyl radical is also understood to mean saturated as well as unsaturated heterocyclic compounds, preferably 5-7-membered heterocyclic compounds, that contain at least one heteroatom, preferably nitrogen, oxygen and/or sulfur, particularly preferably nitrogen and/or oxygen. The saturated heterocyclic compounds are preferably 1,4-dioxane, tetrohydrofuran or 1,4 thioxane. The unsaturated heterocyclic compounds are preferably furan, thiophene, pyridine, pyrimidine, thiazole, oxazole, isoxazole, pyridazine, pyrazine, quinoline, isoquinoline, phthalazine or quinazoline.
Particularly preferred are the following substituted 2-benzyl-3-dimethylamino-1-phenylpropane derivatives:
(E)-(2RS)-(3RS)-3-benzyl-4-dimethylamino-2-(3-methoxyphenyl)-butan-2-ol or the corresponding hydrochloride
(2RS)-3-[1-(1-benzyl-2-dimethylaminoethyl)-vinyl]-phenol or the corresponding hydrochloride
(2RS)-1-(3-benzyloxyphenyl)-2-dimethylaminomethyl-3-phenylpropan-1-one or the corresponding hydrochloride
E-(2RS)-(3RS)-2-benzyl-1-dimethylamino-3-(3-methoxyphenyl)-pentan-3-ol or the corresponding hydrochloride
(3RS)-2-benzyl-1-(4-chlorophenyl)-3-dimethylaminopropan-1-one or the corresponding hydrochloride
E-(2RS)-(3RS)-2-benzyl-3-(3-benzyloxyphenyl)-1-dimethylaminopentan-3-ol or the corresponding hydrochloride
E-(2RS)-(3RS)-3-(2-benzyl-3-dimethylamino-1-hydroxypropyl)-phenol or the corresponding hydrochloride
E-(2RS)-(4RS)-3-benzyl-2-(3-benzyloxyphenyl)-4-dimethylaminobutan-2-ol or the corresponding hydrochloride
E-(2RS)-(3RS)-3-(2-benzyl-3-dimethylamino-1-methyl-1-hydroxypropyl)-phenol or the corresponding hydrochloride
E-(2RS)-(3RS)-3-(2-benzyl-3-dimethylamino-1-ethyl-1-hydroxypropyl)-phenol or the corresponding hydrochloride
(Z/E)-(2RS)-3-(1-(1-benzyl-3-dimethylaminoethyl)-propenyl]-phenol or the corresponding hydrochloride
(2RS)-3-dimethylamino-2-(4-methoxybenzyl)-1-(3-methoxyphenyl)-propan-1-one or the corresponding hydrochloride
Z-(1RS)-(2RS)-2-benzyl-1-(4-chlorophenyl)-3-dimethylamino-1-(3-methoxyphenyl)-propan-1-ol or the corresponding hydrochloride
E-(2RS)-(3RS)-2-benzyl-3-(4-chlorophenyl)-1-dimethylaminopentan-3-ol or the corresponding hydrochloride
E-(2RS)-(3RS)-3-benzyl-2-(4-chlorophenyl)-4-dimethylamino-1-phenylbutan-2-ol or the corresponding hydrochloride
Z-(2RS)-(3RS)-3-benzyl-2-(4-chlorophenyl)-4-dimethylamino-1-phenylbutan-2-ol or the corresponding hydrochloride
E-(2RS)-(3RS)-2-benzyl-3-dimethylamino-1,1-bis-(3-methoxyphenyl)-propan-1-ol or the corresponding hydrochloride
E-(2RS)-(3RS)-2-dimethylaminomethyl-3-(3-methoxyphenyl)-1-phenylhexen-5-ol or the corresponding hydrochloride
(2RS)-2-benzyl-3-dimethylamino-1-(3-trifluoromethylphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-3-dimethylamino-1-(3-hydroxyphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-1-(3,5-dimethoxyphenyl)-3-dimethylaminopropan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-1-(2,5-dimethoxyphenyl)-3-dimethylaminopropan-1-one or the corresponding hydrochloride
(1RS)-(2RS)-2-benzyl-1-(3-methoxyphenyl)-N,N-dimethylpropan-1,3-diamine or the corresponding hydrochloride
(2RS)-2-benzyl-1-(2,3-dimethoxyphenyl)-3-dimethylaminopropan-1-one or the corresponding hydrochloride
(+)-(R)-2-benzyl-3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one or the corresponding hydrochloride
(xe2x88x92)-(S)-2-benzyl-3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-1-(2,3-dichlorophenyl)-3-dimethylaminopropan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-1-(2,5-dichlorophenyl)-3-dimethylaminopropan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-3-dimethylamino-1-(2,3,4-trimethoxyphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-3-dimethylamino-1-(3,4,5-trimethoxyphenyl)-propan-1-one or the corresponding hydrochloride
Z-(2RS)-[2-benzyl-3-(3-methoxyphenyl)-pent-3-enyl]-dimethylamine or the corresponding hydrochloride
(2RS)-2-benzyl-1-(2,5-dihydroxyphenyl)-3-dimethylaminopropan-1-one or the corresponding hydrochloride
E-(2RS)-(3RS)-2-dimethylaminomethyl-3-(3-methoxyphenyl)-1,3-diphenylpropan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-3-dimethylamino-1-(2-methoxyphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-3-dimethylamino-1-naphthalen-2-yl-propan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-3-dimethylamino-1-phenanthren-3-yl-propan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-3-dimethylamino-1-(2-hydroxyphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-3-dimethylamino-1-(2-fluorophenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-3-dimethylamino-1-(3-methylsulfanylphenyl)-propan-1-one or the corresponding hydrochloride
E-(2RS)-(3RS)-[2-benzyl-3-(3-methoxyphenyl)-pentyl]-dimethylamine or the corresponding hydrochloride
(Z/E)-(2RS)-(3RS)-[2-benzyl-3-(3-methoxyphenyl)-pentyl]-dimethylamine or the corresponding hydrochloride
(2RS)-2-benzyl-3-dimethylamino-1-(2-hydroxy-5-methoxyphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-3-(2-benzyl-3-dimethylaminopropionyl)-benzonitrile or the corresponding hydrochloride
(2RS)-(3RS)-2-dimethylaminomethyl-1,3,3-tris-(3-methoxyphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-1-biphenyl-3-yl-3-dimethylaminopropan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-3-dimethylamino-1-(6-methoxynaphthalen-2-yl)-1-one or the corresponding hydrochloride
(2RS)-(3RS)-2-dimethylaminomethyl-1,3-bis-(3-methoxyphenyl)-3-phenylpropan-1-one or the corresponding hydrochloride
Z-(2RS)-(3RS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)-3,4-diphenylbutan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-3-dimethylamino-1-(6-hydroxynaphthalen-2-yl)-propan-1-one or the corresponding hydrochloride
(2RS)-(3RS)-3-(2-benzyl-3-dimethylamino-1-ethylpropyl)-phenol or the corresponding hydrochloride
(2RS)-2-benzyl-1-biphenyl-2-yl-3-dimethylaminopropan-1-one or the corresponding hydrochloride
(2RS)-(3RS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)-3-phenylpentan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-1-(2-chloro-4-fluorophenyl)-3-dimethylamino-propan-1-one or the corresponding hydrochloride
(2RS)-2-dimethylaminomethyl-1-[(1RS)-3-(1-hydroxy-3-phenylpropyl)-phenyl]-3-phenylpropan-1-one or the corresponding hydrochloride
(2RS)-3-dimethylamino-2-(2-fluorobenzyl)-1-(3-methoxyphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-3-dimethylamino-2-(3-fluorobenzyl)-1-(3-methoxyphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-3-dimethylamino-2-(4-fluorobenzyl)-1-(3-methoxyphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-(3RS)-2-dimethylaminomethyl-3,3-bis-(3-methoxyphenyl)-1-naphthalen-2-yl-propan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one or the corresponding hydrochloride
Z-(2RS)-(3RS)-2-dimethylaminomethyl-1,3-diphenylpentan-1-one or the corresponding hydrochloride
(2RS)-(3RS)-2-dimethylaminomethyl-1,3-diphenyl-3-p-tolylpropan-1-one or the corresponding hydrochloride
(2RS)-(3RS)-2-dimethylaminomethyl-1,3,6-triphenylhexan-1-one or the corresponding hydrochloride
E-(2RS)-(3RS)-3-benzyl-4-dimethylamino-2-(3-methoxyphenyl)-1-phenylbutan-2-ol or the corresponding hydrochloride
(2RS)-(3RS)-3-benzyl-4-dimethylamino-1,1,1-trifluoro-2-(3-methoxyphenyl)-butan-2-ol
E-(2RS)-[2-benzyl-3-(3-methoxyphenyl)-pent-3-enyl]-dimethylamine or the corresponding hydrochloride
(+)-(R)-2-benzyl-3-dimethylamino-1-(3-hydroxyphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-3-dimethylamino-2-(3-methylbenzyl)-1-(3-methoxyphenyl)-propan-1-one or the corresponding hydrochloride
(xe2x88x92)-(S)-2-benzyl-3-dimethylamino-1-(3-hydroxyphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-2-dimethylamino-2-(3-fluorobenzyl)-1-(3-hydroxyphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-3-dimethylamino-2-(3-methoxybenzyl)-1-(3-methoxyphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-3-dimethylamino-1-(4-methoxy-2,3-dimethylphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-2-(3-chlorobenzyl)-3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one or the corresponding hydrochloride
(2RS)-3-dimethylamino-1-(3-methoxyphenyl)-2-(3-methylbenzyl)-propan-1-one or the corresponding hydrochloride
(2RS)-2-benzyl-3-dimethylamino-1-(2,4,6-trimethylphenyl)-propan-1-one or the corresponding hydrochloride
(S)-(xe2x88x92)-3-dimethylamino-1-(3-methoxyphenyl)-2-(3-fluorobenzyl)-propan-1-one or the corresponding hydrochloride
(R)-(+)-3-dimethylamino-1-(3-methoxyphenyl)-2-(3-fluorobenzyl)-propan-1-one or the corresponding hydrochloride
(RS)-3-dimethylamino-1-(3-hydroxyphenyl)-2-(3methylbenzyl)-propan-1-one or the corresponding hydrochloride
(RS)-2-benzyl-1-(2,4-dichlorophenyl)-3-dimethylaminopropan-1-one or the corresponding hydrochloride
(RS)-3-dimethylamino-2-(4-flurobenzyl)-1-(3-hydroxyphenyl)-propan-1-one or the corresponding hydrochloride
(RS)-1-(3-methoxyphenyl)-2-methylaminomethyl-3-m-tolylpropan-1-one or the corresponding hydrochloride
(RS)-2-(3-chlorobenzyl)-3-dimethylamino-1-(3-hydroxyphenyl)-propan-1-one or the corresponding hydrochloride
(RS)-3-(3,4-difluorophenyl)-2-dimethylaminomethyl-1-(3-methoxyphenyl)-propan-1-one or the corresponding hydrochloride
(RS)-3-(3-fluorophenyl)-1-(3-methoxyphenyl)-2-methylaminomethyl-1-propan-1-one or the corresponding hydrochloride
(RS)-3-(3-fluorophenyl)-1-(3-hydroxyphenyl)-2-methylaminomethyl-1-propan-1-one or the corresponding hydrochloride
(RS)-1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-dimethylamino-methyl-3-phenylpropan-1-one or the corresponding hydrochloride
(RS)-2-dimethylaminomethyl-1-(3-phenoxyphenyl)-3-phenylpropan-1-one or the corresponding hydrochloride
(RS)-3-(3,4-difluorophenyl)-2-dimethylaminomethyl-1-(3-hydroxyphenyl)-propan-1-one or the corresponding hydrochloride
(RS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)-3-(3-trifluoromethylphenyl)propan-1-one or the corresponding hydrochloride
(RS)-2-dimethylaminomethyl-1-(3-hydroxyphenyl)-3-(3-trifluoromethylphenyl)propan-1-one or the corresponding hydrochloride
Z/E-(2RS)(3RS)-1-(4-chlorophenyl)-3-dimethylaminomethyl-2-(3-methoxyphenyl)-4-phenylbutan-2-ol or the corresponding hydrochloride
Z/E-(2RS)(3RS)-1-(3-chlorophenyl)-3-dimethylaminomethyl-2-(3-methoxyphenyl)-4-phenylbutan-2-ol or the corresponding hydrochloride
Z/E-(2RS)(3RS)-1-(2-chlorophenyl)-3-dimethylaminomethyl-2-(3-methoxyphenyl)-4-phenylbutan-2-ol or the corresponding hydrochloride
The invention also provides processes for preparing substituted 3-amino-2-benzyl-1-phenylpropane derivatives of the general formula I, in which R0 and R3 together denote a group xe2x95x90O and R1 denotes H, R2 and R4 to R6 as well as R12 have the meanings specified in the general formula I, which processes are characterised in that substituted aldehydes of the general formula II 
are reacted in the presence of a magnesium in a Grignard reaction with compounds of the general formula III 
wherein X denotes Br, Cl or I, preferably Br, to form compounds of the general formula IV 
and are purified and isolated by conventional methods.
The compounds of the general formula IV are oxidised in solution, preferably in aqueous or ethereal solution, with an oxidising agent, preferably with inorganic salts, particularly preferably with potassium dichromate or sodium hydrochlorite to form compounds of the general formula V 
The compounds of the general formula V are then reacted with an iminium salt of an aldehyde and a compound of the general formula NH(R12)2.HCl, wherein R12 has the meaning according to the general formula I, in a Mannich reaction to form compounds of the general formula VI 
and are purified by conventional methods and are isolated as salts of physiologically compatible acids.
The invention furthermore provides processes for preparing substituted 3-amino-2-benzyl-1-phenylpropane derivatives of the general formula I, wherein R0 denotes OH and R1 denotes H, and R2 to R6 as well as R12 have the meanings specified in the general formula I, which processes are characterised in that compounds of the general formula VI are reacted with an organometallic compound of the general formula R3MX, wherein M denotes Li, Mg or Zn and X denotes Cl, Br or I, to form compounds of the general formula VII 
In the reaction of a xcex2-dimethylaminoketone of the general formula VI with an organometallic compound of the general formula R3MX, tertiary alcohols of the general formula VII are preferably obtained having a configuration in which the amino group is arranged in the cis, threo (or Z, E) position to the hydroxyl group. The resulting tertiary alcohols of the general formula VII can be obtained in a diastereomer pure form by column chromatography separation or by crystallisation of their salts, preferably of the hydrochlorides.
The invention furthermore provides processes for preparing substituted 3-amino-2-benzyl-1-phenylpropane derivatives of the general formula I, wherein R0 and R3 together denote a group xe2x95x90CHR11 and R1 denotes H, and R2 and R4 to R6 as well as R12 have the meanings specified in the general formula I, which processes are characterised in that compounds of the general formula VII are treated with hydrogen bromide and the corresponding olefins of the general formula VIII 
are isolated as salts of physiologically compatible acids.
The invention further provides processes for preparing substituted 3-amino-2-benzyl-1-phenylpropane compounds of formula I, wherein R0 denotes H and R1 denotes H, and R2 to R6 and also R12 have the meanings specified in formula I, which processes are characterised in that compounds of formula VIII are hydrogenated ion the presence of a palladium/carbon catalyst with hydrogen to form corresponding alkanes of formula IX 
and the latter are isolated as salts of physiologically compatible acids.
The invention further provides processes for preparing substituted 3-amino-2-benzyl-1-phenylpropane derivatives of the general formula I, wherein R0 and R3 together denote a group xe2x95x90O and R1xe2x89xa0H, and R2 as well as R4 to R6 have the meanings specified in the general formula I, which processes are characterised in that substituted acetaldehydes of the general formula X 
are reacted with substituted benzaldehydes of the general formula XI 
in an aldol condensation to form substituted 1,3-diphenylpropenones of the general formula XII 
which are purified and isolated by conventional methods.
These compounds of formula XII are reacted with compounds that had been converted from compounds of the formula R1Br with magnesium into a Grignard compound and then by a transmetallisation with copper(1) iodide into the corresponding cuprates to form an enolate, and the enolate is then reacted in situ with the iminium salt of an aldehyde and a compound of the general formula NH(R12)2.HCl, wherein R12 has the meaning according to the general formula I. The resulting compounds of formula XIII 
are purified by conventional methods and are isolated as salts of physiologically compatible acids.
The invention furthermore provides processes for preparing substituted 3-amino-2-benzyl-1-phenylpropane compounds of formula I, wherein R0 denotes OH and R1xe2x89xa0H, and R2 to R6 as well as R12 have the meanings specified for formula I, which processes are characterised in that compounds of formula XIII are reacted with compounds of the formula R3MX, wherein M denotes Li, Mg or Zn and X denotes Cl, Br or I, and the resulting compounds of formula XIV 
are purified by conventional methods and are isolated as salts of physiologically compatible acids.
The invention also provides processes for preparing substituted 3-amino-2-benzyl-1-phenylpropane compounds of formula I, wherein R0 and R3 together denote a group xe2x95x90CHR11 and R1xe2x89xa0H, and R2 and R4 to R6 as well as R12 have the meanings specified for formula I, wherein compounds of formula XIV are treated with hydrogen bromide to obtain corresponding olefins of formula XV 
and the resulting olefins are purified by conventional methods and are isolated as salts of physiologically compatible acids.
The invention also provides processes for preparing substituted 3-amino-2-benzyl-1-phenylpropane compounds of formula I, wherein R0 denotes H and R1xe2x89xa0H, and R2 to R6 as well as R12 have the meanings specified for formula I, wherein compounds of formula XV are hydrogenated with hydrogen in the presence of a palladium/carbon catalyst to form the corresponding alkanes of formula XVI 
and the latter are purified by conventional methods and isolated as salts of physiologically compatible acids.
The invention furthermore provides processes for preparing compounds of formula I, wherein R4 and/or R5 and/or R6 denote an OH group and R0 to R3 as well as R12 have the meanings specified for formula I, wherein compounds of formula I, wherein R4 and/or R5 and/or R6 denote a methoxy group and R0 to R3 as well as R12 have the meanings specified for formula I, are treated with methionine in methanesulfonic acid, in particular at a temperature xe2x89xa760xc2x0 C. (J. C. S. Perkin I 1977, 2288-2289).
The compounds of formula I can be converted in a known manner into their salts by reaction with physiologically compatible acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid. The salt formation is preferably carried out in a solvent, for example diethyl ether, diisopropyl ether, alkyl acetates, acetone and/or 2-butanone. Moreover, trimethylchlorosilane in methyl ethyl ketone is suitable for preparing the hydrochlorides.
The substituted 3-amino-2-benzyl-1-phenylpropane compounds of formula I according to the invention are toxicologically safe and accordingly represent suitable pharmaceutical active constituents.
The invention furthermore provides pharmaceutical products that contain as active substance at least one substituted 3-amino-2-benzyl-1-phenylpropane derivative of the general formula I and/or their enantiomers, diastereomers, bases or salts of physiologically compatible acids and optionally further active constituents and/or auxiliaries. Excluded are compounds of the general formula Ixe2x80x2
wherein the radicals R0 and R3 together denote the group xe2x95x90O and R, R2, R4 to R6 and R4xe2x80x2 to R6xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 and R3 together denote the group xe2x95x90O, R6 denotes the group OCH3, and R1, R2, R4, R5 and R4xe2x80x2 to R6xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as hydrochloride,
wherein R0 and R3 together denote the group xe2x95x90O, R6xe2x80x2 denotes the group OCH3, and R1, R2, R4 to R6, R4xe2x80x2 and R5xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 and R3 together denote the group xe2x95x90O, R6xe2x80x2 denotes Cl, and R1, R2, R4 to R6, R4xe2x80x2 and R5xe2x80x2 denote H, and also the radicals R12 in each case denote CH3,
wherein R0 and R3 together denote the group xe2x95x90O, R5xe2x80x2 and R6xe2x80x2 in each case denote the group OCH3, and R1, R2, R4 to R6 and R4xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as hydrochloride,
wherein R0 and R3 together denote the group xe2x95x90O, R4, R6 and R6xe2x80x2 in each case denote the group OCH3, and R1, R2, R5, R4xe2x80x2 and R5xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as hydrochloride,
wherein R0 denotes OH, R3 denotes H, CH3, unbranched C3H7, unbranched C5H11, cyclohexyl, phenyl or benzyl, and R1, R2, R4 to R6 and R4xe2x80x2 to R6xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochlorides,
wherein R0 denotes OH, R3 denotes C2H5, and R1, R2, R4 to R6 and R4 to R6xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride and the corresponding methyliodide,
wherein R0 denotes OH, R3 denotes phenyl, R6 denotes Cl, R1, R2, R4, R5 and R4xe2x80x2 to R6xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 denotes OH, R3 denotes phenyl, R6xe2x80x2 denotes Cl, R1, R2, R4 to R6, R4xe2x80x2 and R5xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 denotes OH, R3 denotes phenyl, R5xe2x80x2 , R6xe2x80x2 in each case denote the group OCH3, R1, R2, R4 to R6 and R4xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as hydrochloride,
wherein R0 denotes OH, R3 denotes phenyl, R6 denotes the group OCH3, R1, R2, R4, R5 and R4xe2x80x2 to R6xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 denotes OH, R3 denotes phenyl, R6xe2x80x2 denotes the group OCH3, R1, R2, R4 to R6xe2x80x2 R4xe2x80x2 and R5xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride and the corresponding methyliodide,
wherein R0 denotes OH, R3 denotes phenyl, R6 and R6xe2x80x2 in each case denote the group OCH3, R1, R2, R4, R5, R4xe2x80x2 and R5xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 denotes OH, R6xe2x80x2 denotes OCH3, R1 to R6, R4xe2x80x2 and R5xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0, R1, R2, the radicals R4 to R6, the radicals R4xe2x80x2 to R6xe2x80x2 in each case denote H, the radical R3 denotes phenyl, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R1, R2, the radicals R4 to R6, the radicals R4xe2x80x2 to R6xe2x80x2 in each case denote H, the radicals R3 and R0 together denote the group xe2x95x90CHR11 and also the radical R11 and in each the radicals R12 denote CH3, as hydrochloride, and
wherein R1, R2, the radicals R4 to R6, the radicals R4xe2x80x2 to R6xe2x80x2 in each case denote H, the radicals R3 and R0 together denote the group xe2x95x90Nxe2x80x94OH and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride.
The invention further provides for the use of at least one substituted 3-amino-2-benzyl-1-phenylpropane derivative of the general formula I and/or their enantiomers, diastereomers, bases or salts of physiologically compatible acids for preparing a pharmaceutical product for treating pain, the compounds of the general formula Ixe2x80x2 being excluded,
wherein the radicals R0 and R3 together denote the group xe2x95x90O and R1, R2, R4 to R6 and R4xe2x80x2 to 6, denote H and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 and R3 together denote the group xe2x95x90O, R6 denotes the group OCH3 and R1, R2, R4, R5 and R4xe2x80x2 to R6xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as hydrochloride,
wherein R0 and R3 together denote the group xe2x95x90O, R6xe2x80x2 denotes the group OCH3 and R1, R2, R4 to R6, R4xe2x80x2 and R5xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 and R3 together denote the group xe2x95x90O, R6xe2x80x2 denotes Cl and R1, R2, R4 to R6, R4xe2x80x2 and R5xe2x80x2 denote H, and also the radicals R12 in each case denote CH3,
wherein R0 and R3 together denote the group xe2x95x90O, R5xe2x80x2 and R6xe2x80x2 in each case denote the group OCH3, and R1, R2, R4 to R6 and R4xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as hydrochloride,
wherein R0 and R3 together denote the group xe2x95x90O, R4, R6 and R6xe2x80x2 in each case denote the group OCH3, and R1, R2, R5, R4xe2x80x2 and R5xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as hydrochloride,
wherein R0 denotes OH, R3 denotes H, CH3, unbranched C3H7, unbranched C5H11, cyclohexyl, phenyl or benzyl, and R1, R2, R4 to R6 and R4xe2x80x2 to R6xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochlorides,
wherein R0 denotes OH, R3 denotes C2H5, and R1, R2, R4 to R6 and R4xe2x80x2 to R6xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride and the corresponding methyliodide,
wherein R0 denotes OH, R3 denotes phenyl, R6 denotes Cl, R1, R2, R4, R5 and R4xe2x80x2 to R6xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 denotes OH, R3 denotes phenyl, R6xe2x80x2 denotes Cl, R1, R2, R4 to R6, R4xe2x80x2 and R5xe2x80x2 denote H, and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 denotes OH, R3 denotes phenyl, R5xe2x80x2, R6xe2x80x2 in each case denote the group OCH3, R1, R2, R4 to R6 and R4xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as hydrochloride,
wherein R0 denotes OH, R3 denotes phenyl, R6 denotes the group OCH3, R1, R2, R4, R5 and R4xe2x80x2 to R6xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 denotes OH, R3 denotes phenyl, R6xe2x80x2 denotes the group OCH3, R1, R2, R4 to R6, R4xe2x80x2 and R5xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride and the corresponding methyliodide,
wherein R0 denotes OH, R3 denotes phenyl, R6 and R6xe2x80x2 in each case denote the group OCH3, R1, R2, R4, R5, R4xe2x80x2 and R5xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0 denotes OH, R6xe2x80x2 denotes OCH3, R1 to R6, R4xe2x80x2 and R5xe2x80x2 denote H and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride,
wherein R0, R1, R2 the radicals R4 to R6, the radicals R4xe2x80x2 to R6xe2x80x2 in each case denote H, the radical R3 denotes phenyl and also the radicals R12 in each case denote CH3, as well as the corresponding hydrochloride, and
wherein R1, R2, the radicals R4 to R6, the radicals R4xe2x80x2 to R6xe2x80x2 in each case denote H, the radical R3 and R0 together denote the group xe2x95x90CHR11 and also the radical R11 and in each case the radicals R12 denote CH3, as hydrochloride.
The invention furthermore provides for the use of at least one substituted 3-amino-2-benzyl-1-phenylpropane derivative of the general formula I and/or their enantiomers, diastereomers, bases or salts of physiologically compatible acids for preparing a pharmaceutical product for treating urinary incontinence, inflammations, allergies, depression, drug or alcohol misuse, gastritis, diarrhea, cardiovascular conditions, respiratory conditions, coughing, psychogenic disorders or epilepsy.
In order to prepare appropriate pharmaceutical formulations, there are used in addition to at least one substituted 3-amino-2-benzyl-1-phenylpropane derivative of the general formula I, also excipients, fillers, solvents, diluents, dyes and/or binders. The choice of auxiliaries, as well as the amounts thereof to be used, depends on whether the pharmaceutical product is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or topically, for example to treat infections of the skin, mucous membranes or eyes. For oral application suitable preparations are in the form of tablets, sugar-coated tablets, capsules, granules, drops, ointments and syrups, while for parenteral, topical and inhalative application suitable preparations are in the form of solutions, suspensions, easily reconstitutable dry preparations, as well as sprays.
Compounds according to the invention of the general formula I in a depot in dissolved form or in plaster, optionally with the addition of agents promoting skin penetration, are suitable percutaneous application preparations. Preparations suitable for oral or percutaneous administration can provide for the delayed release of the compounds of formula I according to the invention.
The amount of active substance to be administered to the patient varies depending on the patient""s weight, method of application, medical indications and the severity of the condition. Normally 50 to 500 mg/kg of at least one 3-amino-2-benzyl-1-phenylpropane derivative of the general formula I are administered.